Methods for diagnosing and treating dysautonomia and other dysautonomic conditions

ABSTRACT

Methods for aiding in the diagnosis of dysautonomic disorders and dysautonomic conditions and methods for treating individuals diagnosed as having a dysautonomic disorder or a dysautonomic condition. In one aspect, a diagnosis method comprising analyzing a stool sample of an individual for the presence of a biological marker wherein the quantity of the biological marker is an indication of whether the invidual has, or can develop, a dysuatonic disorder or dysautonomic condition, as well as a therapuetic method for treating a dysautonomic disorder or dysautonomic condition by administration of, e.g., secretin, neuropeptides, peptides and/or digestive enzymes.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application is based on, and claims the benefit of, U.S.Provisional Application No. 60/224,991, filed on Aug. 14, 2000, which isfully incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention generally relates to methods for aiding inthe diagnosis of dysautonomic disorders and dysautonomic conditions andmethods for treating individuals diagnosed as having a dysautonomicdisorder or a dysautonomic condition. More particularly, the inventionrelates to a diagnosis method comprising analyzing a stool sample of anindividual for the presence of a biological marker (or marker compound)that provides an indication of whether the invidual has, or can develop,a dysuatonic disorder or dysautonomic condition, as well as atherapuetic method for treating a dysautonomic disorder or dysautonomiccondition by administration of, e.g., secretin, neuropeptides, peptidesand/or digestive enzymes.

BACKGROUND

[0003] Familial Dysautonomia (FD), which is also known as Riley-daysyndrome, is an autosomal recessive sensory neuropathy that affectsapproximately 1 in 4,000 individuals of Ashkenazi Jewish descent. Thisdisorder is marked by a reduction of unmyelinated and small myelinatedfibers as well as a reduction of dopamine-beta-hyrozylase in the bood.FD decreases both the sympathetic neurons and the peripheral smallfibers that modulate temperature regulation. It is thought to arise fromboth the failure of intrauterine development of neurons and theirpostnatal development. Symptomotology of FD includes, e.g., renaldisease, corneal ulcerations, mental retardation, loss of pain andvibratory senses, in coordination of movements, diarrhea, esophagealreflux, secretory diarrhea, gastrointestinal paresis, hypotension,facial abnormalities, altered dentition, increased salivary secretion,abnormalities of the sweat glands, bowel distension, fecal impaction,prolonged QT intervals (>440), risk of sudden death, and orthostaticsyncope. Further features include decreased pain sensation, decreasedtemperature regulation, difficulty feeding, lack of overflow tears whilecrying, recurrent pnetimonias, scoliosis or hyperkyhsis, increasedsweating and skin blotching, decreased stature, as well as otherconditions associated with autonomic dysfunction.

[0004] Currently the underlying biochemical and genetic defects whichcause the FD disorder are unknown. The gene which causes this disorderhas been mapped to chromosome 9, the q31-33 region. Presently, there isno prenatal screening test for this condition, and there is no earlydetection of the condition other than the presence of symptomotology.

[0005] There are a plethora of dysautonmic disorders or disorders inwhich symptomologies of autonomic dysfunction are manifest. Forinstance, Parkinson's disease is marked by mild to severe autonomicdysfunction including changes in gait, tremor, discoordination,increased salivary flow, and overall loss of autonomic function.Additionally, changes in executive function are typically noted in aParkinson's patient, often times allowing the patient to appear ashaving Alzheimer's disearse and resulting in misdiagnosis. Executivefunction disorders are also found in autistic children.

[0006] It is known that Parkinson's disease is caused by a deficientstate of levo-dopamine in the brain. More specifically, levo-dopainduced dyskinesis in Parkinson's patients is thought to be a result ofdenervation of the substantia nigra. To this date, medical science hasnot found a substrate that would allow an injectable form of 1-dopa toreach the brain and successfully cross the blood brain barrier. Thecurrent dopamine replacement therapy is aimed at either directreplacement or mimicking the action at the dopamine receptor sites inthe brain. Sinemet™ and Sinemet CR™ are the two major drugs suited tothat end. While the levodopa-therapy can create some benficial changsinitially, those changes generally wane over time, and produce otherproblems such as severe sleep disturbance, dyskinesias, and constantnausea. Medical approaches to Parkinson's disease include surgicaldestruction of the tissue of the brain and the insertion ofmicroelectrodes (deep brain electrical stimulation) to effected portionsof the brain. The insertion of electrodes has the advantage of beingreversible. These interventions, however, are generally transient andneither produce a permanent change in the Parkinsonsian state norreverse the effects of the disease.

[0007] Parkinson's is widespread throughout the Western hemisphere andwas first reported by physician James Parkinson in 1817. Parkison'sdisease is first detected as a tremor in a limb, and ultimatelyprogresses to include 3 manifestatons: (i) rigidity, which ischaracterized by “cog-wheel” like movement and “lead-pipe” rigidity;(ii) bradykinesia or slowness in movement, and (iii) posturalinstability associated with a stooped stance and an impaired gait. Thesealtered movements are features of the motor dysfunction, but in additionthere can also be a mental impairment in as many as 40% of allParkinson's patients.

[0008] Some authors suggest that Parkinson's disease is a multifactorneurodegenerative disorder, which evolves due to excesive oxidation. Thesubstantia nigra is susceptible to oxidative damage, which supports thistheory of the formation of Parkinson's disease. Abnormalities of theoxidative phosphorlation impair the mitochondria of the substantianigra, and intensify free radical generation.

[0009] While the dyskinesias and loss of executive functioning of thebrain receive the most significant mention with respect to Parkinson's,other manifestations exist that are associated with autonomicdysfunction, which are often poorly understood. Some of thesemanifestations include, e.g., esophageal reflux, diarrhea, and othergastrointestinal dysfunction. In addition, excessive sweating, sleepdisturbances and still other symptoms of Parkinson's disease are verysimilar to those found in Familial Dysautonomia.

[0010] Guillaine-Barre Syndrome (GBS) is characterized as an acuteautoimmune polyradiculopathy. It generally manifests as a flaccidparesis coupled with areflexia, sensory loss and disturbance, as well asan elevated cerebrospnal fluid protein level. There are multiplevariations of GBS, each of which displays a specific subgrouping ofsymptoms, including those of the Miler Fisher Syndrome group. GBS seenprimarily in the United States constitutes a subtype best characterizedas a demyelinating type. In the past, GBS was thought to be caused bynumerous factors such as the presence of an antecedent viral infection.The most recent hypothesis points to the presence of an antecedentinfection of Campylobacter jejuni gastroeriteritis. It is furtherpostulated that the presence of this infection produces inflammation ofthe brain and nervous system and gastrointestinal tract.

[0011] Further, a correlation between ketoacidosis and GBS was recentlydiscovered, whereby a patient with diarrhea and fever in a comatosestate had a serum blood glucose level of 672 mg/dl, with the presence ofurinary ketone bodies. This pancreatic role in the potential formationof GBS (as well as other dysautonomic conditions) is of note and isaddressed by the present invention.

[0012] Furthermore, tumors of differing types can also producedysautonomic symptomotology. For example, pheochromocytoma is awell-encapsulated, lobular, vascular tumor, which can occur anywhere inthe body. It is made up of chromaffin tissue of the adrenal medulla, orsympathetic paraganglia. Hypertension is the most apparent symptom,reflecting the increased secretion of epinephrine and norepinephrine,and may be either persistent or intermittent. Attacks may occur anywherefrom every few months to several times daily, and typically last lessthan five minutes. Physical and emotional stresses can initiate anattack. During severe attacks, patients may experience headache,sweating, apprehension, palpation, tremor, pallor or flushing of theface, nausea and vomiting, pain in the chest and abdomen, andparesthesias of the extremities, weight loss, and orthostatichypotension. Inflammation is a hallmark of this condition.Interestingly, these symptoms are common to many other dysautonomicconditions. Chemodectoma is another type of tumor, characterized as anybenign, chromaffin-negative tumor of the chemoreceptor system. The mostcommon types of chemodectoma are the carotid (the principal artery inthe neck) body tumor and the glomus jugulare tumor, and it is also knownas nonchromaffin paraganglioma.

[0013] Neuroblastoma, a type of sarcoma, consists of malignantneuroblasts, which typically arise in the autonomic nervous system, orin the adrenal medulla. It is considered a type of neuroepithelial tumorand affects mostly infants and children up to the age of ten. Eightyfive percent of cases occur prior to age six, and arise from immatureundifferentiated neuroblasts of neural crest origin. Two-thirds ofneuroblastomas occur in an adrenal gland, but may also appear wheresympathetic nerves are present, such as in the chest, pelvis, abdomen,and neck. Symptoms may include fever, weight loss, weakness, abdominaldiscomfort, anorexia, anemia, bone pain, proptosis, pallor, periorbitalecchymoses, easy bruising, neurological manifestations, and metasticsubcutaneous nodules, and possible hypertension.

[0014] Next, Dopamine-b-Hydroxalase Deficiency is characterized by bothsympathetic noradrenergic denervation and adrenomedullary failure, andintact vagal and sympathetic cholinergic function. It is a rare,congenital, non-hereditary form of severe orthostatic hypotension,caused by complete absence of Dopamine-b-Hydroxylase, the enzymeinvolved in the conversion of dopamine to norepinephrine. The presenceof orthostatic hypotension has not been documented in those who areafflicted with Db H deficiency prior to the age of 20. However, duringchildhood, impaired exercise tolerance, fatigue, and episodes offainting and syncope, are frequently present. Symptoms from orthostaticintolerance worsen in late adolescence and in early adulthood. Patientsexperience more intense symptoms due to orthostatic intolerance in themorning hours, heat, and after alcohol consumption, though they do notexperience symptoms after eating. Upon physical examination, patientsmay reveal a low normal (supine) blood pressure and a low (supine) heartrate. In the upright position, systolic blood pressure always fallsbelow 80 mm Hg. However, opposite of other forms of autonomic failure,the compensatory rise in heart rate is completely preserved. Sweating isnormal, and the pupils may be somewhat small, but respond to light andaccommodations.

[0015] Baroreflex failure may present itself by essential hypertension,uncontrolled severe hypertension, pheochromocytoma, or, less commonly,damage to the glossopharyngeal or vagal nerves. Patients with baroreflexfailure may have severe hypertension, either sustained or episodic.Blood pressures can reach 170-280/110-135. Accompanying tachycardia maysuggest the diagnosis of pheochromocytoma, which is supported bysensations of warmth and or flushing, palpitations, headache, anddiaphoresis.

[0016] Aromatic L-Amino Acid Decarboxylase Deficiency is a disordercuased by a deficiency of an enzyme of the lyase class that catalyzesthe decarboxylation of aromatic amino acids, notably converting dopa todopamine, tryptophan to tryptamine, and hydroxytryptophan to serotonin.The enzyme is then bound to a pyridoxal phosphate cofactor and occursparticularly in the liver, kidney, brain, and vas deferens. Symptoms ofthe disease may include temperature instability, ptosis of the eyelids,hypersalivation, distal chorea, swallowing difficulties, drowsiness,irritability, truncal hypotonia, oculogyric crises, pinpoint pupils.

[0017] Tetrahydrobiopterin Deficiency is a disorder whereby a defect inenzymes required for the synthesis of catecholomines results in adeficiency of neurotransmitters. Symptoms begin between two and eightmonths-of age, and include unstable body temperature, swallowingdifficulties, hypersalivation, pinpoint pupils, ptosis of the eyelids,decreased mobility, drowsiness, and irritability.

[0018] Familial Paraganglioma Syndrome is another tumor related disease.Due to the chemoreceptor function of the carotid body these, thesetumors were first called chemodectomas or carotid body tumors, thoughcarotidy body paragnanglioma is the most accurate terminology for theselesions. Paragnaglioma tumors that develop from the paraganglia adjacentto the vagus nerve and the jugular bulb are usually described as glomusvagale and glomus jugulare. Paraganglioma tumors are quite rare andaccount for less than 1000 reports cases since 1980.

[0019] As for clinical presentation, cervical paragangliomas includedysphonia, aspiration, hearing loss, dysphagia, tinnitus, pain, chroniccough, and shoulder weakness (due to tumor encroachment on cranialnerves).

[0020] In 1960, two researchers, Dr. Milton Shy at the NationalInstitutes of Health, and Dr. Glen Drager at Baylor College of Medicinein Houston, Tex., described a common set of neurological manifestationsassociated with autonomic failure. Originally called the “Shy-DragerSyndrome,” this complex syndrome is currently referred to as “MultipleSystem Atrophy” or MSA. The American Autonomic Society has defined MSAin the following manner: “MSA is a sporadic, progressive, adult onsetdisorder characterized by autonomic dysfunction, Parkinsonism, andataxia (a failure of muscular coordination) in any combination. Thefeatures of the disorder include Parkinsonism Cerebellar orCorticospinal Signs, Orthostatic Hypotension, Impotence, UrinaryIncontinence or Retention, usually preceding or within two years afterthe onset of the motor symptoms. Parkinsonian and cerebellar featurescommonly occur in combination. However, certain features maypredominate. It is important to note that these manifestations may occurin various combinations and may also evolve over time.

[0021] Next, it is estimated that over 500,000 Americans are afflictedwith Orthostatic Intolerance. Despite the enormity of the number, theseconditions are among the least understood of the autonomic disorders.Orthostatic Intolerance predominately affects younger individuals,particularly females, and often those under the age of thirty-five. Theonset can be sudden, and the impact can be significant on both lifestyleand on the capacity to work. Often, these conditions tend to bemisdiagnosed as either a psychiatric or anxiety-related disorders, dueto the nature of the symptoms.

[0022] Standing upright results in a series of reflexive bodilyresponses, regulated by the Autonomic Nervous System, to compensate forthe effect of gravity upon the distribution of blood. OrthostaticIntolerance results from an inappropriate response to this change inbody position. The normal response for a change in body position isstabilization to the upright position in approximately sixty seconds.During this process, the normal change in heart rate would include anincrease in heart rate of 10 to 15 beats per minute, and an increase indiastolic pressure of 10 mm Hg, with only a slight change in systolicpressure. For those who are afflicted with Orthostatic Intolerance,there is an excessive increase in heart rate upon standing, resulting inthe cardiovascular system working harder to maintain blood pressure andblood flow to the brain.

[0023] The upright posture also brings about a neurohumoral response,involving a change in the levels of vasopressin, renin, angiotensin andaldosterone levels—all of which are involved in the regulation of bloodpressure. Additionally, arterial baroreceptors, particularly those inthe carotid sinus area, play an important role in the regulation ofblood pressure and the response to positional changes. As the heartpumps blood to the body, the left atrium is passively filled with bloodas a result of the force exerted by venous blood pressure. Thebaroreceptors in the left atrium respond proportionately to the pressureexerted by venous blood pressure. Thus, a drop in venous blood pressurewill trigger a compensatory response to increase blood pressure. Anydisruption in any of these processes, or their coordination, can resultin an inappropriate response to an upright position and a series ofsymptoms, possibly including syncope.

[0024] Neurally Mediated Syncope, also known as NeurocardiogenicSyncope, is another disorder characterized by autonomic dysfunction.More specifically, neurocardiogenic syncope is a complex and commondisturbance of the autonomic nervous system that can lead to suddendrops in blood pressure leading to fainting. The medical term forfainting is syncope, coming from the Greek term “syncopa”, meaning “tocut short.” Syncope has many causes, and therefore discerning the exactcause can be difficult. Over the last several years, much has beenlearned about one particular cause of fainting—the disorder now known asneurocardiogenic syncope. Neurocardiogenic syncope is also known asvasovagal syncope or neurally mediated syncope. It describes a transientfailure of the brain to adequately regulate the body's blood pressureand heart rate. The exact cause(s) are still unclear, but a basicunderstanding is evolving. The blood pressure control centers arelocated in the posterior parts of the brain (the brainstem or medulla).Every time a person stands, gravity pulls blood toward the lowerextremities. The brain senses this change and compensates by increasingthe heart rate and tightening (constricting) the blood vessels of thelegs, forcing blood back upward to the brain. These centers in thebrainstem (the autonomic centers), then work as a sort of thermostat toregulate blood pressure. In neurocardiogenic syncope, the systemperiodically breaks down, allowing the blood pressure to fall too low,and causing the brain to lose its blood supply resulting in loss ofconsciousness (fainting). These episodes frequently begin in adolescencefollowing periods of rapid growth, although they can occur at any age.

[0025] Tilt table testing is used to determine a person's susceptibilityto these episodes. This test involves the strapping of a patient to aspecial table, slowly inclining upward to an angle of between 60 and 80degrees, and kept up for around thirty minutes. This provides a constantlow stress (gravity) that should be easily tolerated by a person withnormal autonomic function. However, for patients with poor autonomiccontrol, this relatively mild stress will provoke a sudden fall in heartrate and blood pressure. Some centers will also use a synthetic form ofadrenaline (isoproterenol) as an additional stress.

[0026] Therapy for patients with neurocardiogenic syncope has to beindividualized to fit that person's specific needs. Many patients withneurocardiogenic syncope need only avoid predisposing factors (such asextreme heat or dehydration), though some will require medical therapyto prevent further fainting spells. A variety of different medicationsare used, and no one therapy works for everyone. Some patients mayrequire therapy with low doses of two or three agents in combination,which is often tolerated better than a very high dose of a single agent.

[0027] Sudden Infant Death Syndrome (SIDS), also known as fetal fatalinsomnia, is considered to be of unknown etiology and usually occursduring sleep. The postmortem examination of children who have died as aresult typically does not reveal the cause of death, hence the labelsudden infant death syndrome (SIDS). Recent research has pointed in manydirections with respect to SIDS.

[0028] One theory for the cause of SIDS points again to the role ofreflux. Once thought to be a normal postmortem finding, the evidence ofgastro-espohageal reflux postmortem indicates this as a possiblecontributory factor. Other theories point to the role of nerve damage ornerve malfunction as playing a contributory role in the formation ofSIDS. One study demonstrates a marked prolonged QT interval in those whoare at risk for SIDS. Researchers have documented that a child having aSIDS “attack” who was brought to the hospital was suffering from aprolonged QT interval. Even though the child survived the episode, itrevealed an interesting piece of information.

[0029] The role of hypothalamic failure has also been postulated as acause of SIDS. This failure precludes the infant from sensingtemperature changes in the body, much like that of the child withdysautonomia. It is therefore postulated in accordance with the presentinvention that autonomic dysfunction plays a role, either primary orsecondary, in the incidence of SIDS.

[0030] Interestingly, the dysautonomic conditions described above have agastrointestinal component. Indeed, as with Guillaine-Barre wherein itis postulated that a GI pathogen is a causative factor in the formationof the dysautonomia, it is possible that other dysautonomic conditionshave GI components.

[0031] It was recently discovered that the administration of secretin, agastrointestinal peptide hormone, to children diagnosed with Autismresulted in ameliorating the symptoms associated with Autism. Thisfinding was published in the article by Horvath et al., entitledImproved Social and Language Skills After Secretin Administration InPatients with Autistic Spectrum Disorders, Journal of the Associationfor Academic Minority Physician Vol.9 No.1, pp. 9-15, January, 1998. Thesecretin administration, as described in Horvath, was performed as adiagnostic procedure, i.e., to stimulate pancreaticaobiliary secretionduring an upper gastrointestinal endoscopy, rather than as a therapeuticprocedure. Although the specific mechanism by which the secretinimproved the autistic-related symptoms was not specifically identified,Horvath postulated that secretin may have had a direct or indirecteffect on the central nervous system. What is important, however, isthat this was the first time that gastrointestinal problems of autisticchildren were linked to a possible etiology in Autism.

[0032] It has been found by the present inventor that populations ofautistic children suffer from GI disturbances and other conditions whichare dysautonomic in nature. Thus, in general, these findings arebelieved by the present inventor to be a possible link between theetiology of autism and autonomic dysfunction.

[0033] Accordingly, in view of such findings, a method for determiningwhether an individual suffering from a dysautonomic disorder and/or anydisorder comprising dysautonmic components will benefit from theadministration of secretin, other neuropeptides, peptides and/ordigestive enzymes, would be highly advantageous. In addition, a methodfor aiding in the diagnosis of individuals who may develop dysatonomicdisorders and conditions symptoms is highly desirable.

SUMMARY OF THE INVENTION

[0034] The present invention is directed to methods for aiding in thediagnosis of dysuatonomic disorders and dysautonomic conditions, and fortreating individuals diagnosed as having dysautonomic disorders ordysautonomic conditions inlcuding, but not limited to, FamilialDystautonomia (FD) (or Riley-Day Syndrome), Guillaine-Barre Syndrome(GBS) (acute idiopathic polyneuorpathy), Parkinson's disease, fetalfatal insomnia (FFI), diabetic cardiovascular neuropathy, HereditarySensory and autonomic nueropathy type III (HSAN III), central autonomicdisorders including Parkinson's and multiple system atrophy (Shy-Dragersyndrome), orthostatic intolerance syndrome including mitral valueprolapse, postural tachycardia syndrome (POTS), and idiopathichypovolemia, dysautonomic syndromes and disorders of the catecholeminefamily including baroreflex failure, dopamine-B-Hydroxylase deficiency,pheochromocytoma, chemodectina, familial paraganglioma syndrome,tetrahydrobiopterin deficiency, aromatic-L-amino acid decarboxylasedeficiency, Menke's disease, monoamine oxidase deficiency states, andother disorders of dopamine metabolism, dysautonomic syndromes anddisorders of the cardiovasular system, Chaga's disease, Diabeticautonomc failure, pure autonomic failure, syncope, hypertension,cardiovascular disease, renal disease and SIDS.

[0035] In one aspect, methods are provided for treating all types ofdysautonomia and disorders with autonomic components by theadmininsration of secretin, CCK(Choleystichenin), VIP (VasoactiveIntesinal Peptide), other neuropepetides and peptides, and/or digestiveenzymes.

[0036] In another aspect, diagnostic methods are provided fordetermining whether an indivudual has, or can develop, a dysautonomicdisorder or condition, and for determining whether an individual willbenefit from the adminstration of secretin, CCK, VIP, other neurpeptidesand peptides, and/or digestive enzymes for treating a dysautonomicdisorder or condition. A preferred diagnostic method comprises analyzinga compound in a stool sample of an individual, and correlating theanalysis of the compound with a dysautonomic disorder or condition orlack thereof. In one embodiment, the stool compound comprises apancreatic enzyme such as chymotrypsin, or any compound that provides anindication of either protien digestion or metabolism, pancreaticfunction, or an inflammatory process, or a combination thereof.Preferably, the step of analyzing comprises determining a quantitativelevel of the compound in the stool.

[0037] In another aspect, a method for treating a dyautonomic disorderwith secretin comprises the step of administering to an individualhaving the disorder an effective amount of secretin to improve a symptomof the disorder.

[0038] In yet another aspect, a method for treating a dysautonomicdisorder with secretin comprises the steps of analyzing a compound in astool sample of the individual, wherein the administration of secretinis based on the analysis of the stool sample.

[0039] In another aspect, the stool compound comprises a pancreaticenzyme such as chymotrypsin, or any compound that provides an indicationof either protien digestion or metabolism, pancreatic function, or aninflammatory process, or a combination thereof.

[0040] In yet another aspect, a process of analyzing the stool samplecomprises the steps of measuring a quantitative level of a pancreaticenzyme (such as chymotrypsin) present in the stool sample, and comparingthe measured quantitative level with at least one threshold level todetermine the efficacy of secretin administration to the individual. Inone embodiment, the threshold level is based on a level of thepancreatic enzyme associated with at least one other individual of thesame approximate age that does not have the dysautonomic disorder.

[0041] These and other aspects, features, and advantages of the presentinvention will be described and become apparent from the followingdetailed description of preferred embodiments, which is to be read withthe accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0042]FIG. 1 is a diagram of a family tree illustrating a correlationbetween dysautonomic conditions and other disorders;

[0043]FIG. 2 is a table diagram illustrating measured chymotrypsinlevels of an individual subjected to secretin infusions to treat adysautonomic condition; and

[0044]FIG. 3 is a table diagram illustrating measured chymotrypsinlevels of a plurality of indivudials, some of which having adysautonomic condition.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0045] The present invention is directed to methods for aiding in thediagnosis of dysuatonomic disorders and dysautonomic conditions, and fortreating individuals diagnosed as having a dysautonomic disorder such asFamilial Dystautonomia and other disorders having dysautonomiccomponents. In a preferred embodiment, a method is provided fordetermining the presence of abnormal protein digestion and/or pancreaticdysfunction of an individual, especially a child, by analyzing a stoolsample of the individual for the quanititave levels of one or morepancreatic enzymes, including, but not limited to, chymotrypsin, so asto determine if the individual has, or can develop, a dysautonomicdisorder or condition. Further, a method is provided for determiningwhether the individual is likely to benefit from the administration ofsecretin, CCK, VIP, digestive enzymes, and/or other peptides and/orneuropeptides. Until now, there has been no clear biological marker fordysautonic disorders or conditions to allow early diagnosis or screeningof such disorders or conditions.

[0046] As noted above, it was recently discovered that theadministration of secretin, a gastrointestinal peptide hormone, tochildren diagnosed with Autism resulted in ameliorating the symptomsassociated with Autism. Subsequently, the inventor herein discoveredthat a sub-population of autistic children had, e.g., abnormal topathologic levels of a pancreatic enzyme such as chymotrypsin in theirstools. The inventor herein further discovered that the sub-populationof autistic children who had low levels of fecal chymotryypsin werepositive responders to therapeutic method for treating autism comprisingadministration of, e.g., secretin and/or digestive enzymes. It wasfurther discovered that a sub-population of individuals suffering fromADD (attention deficit disorder) and/or ADHD (attention deficithyperactivity disorder) who had low levels of fecal chymotryypsin werepositive responders to therapeutic method comprising administration of,e.g., secretin and/or digestive enzymes. These findings are described indetail in U.S. patent application Ser. No. 09/466,559, filed Dec. 17,1999, entitled “Methods For Treating Pervasive Development Disorders,”and U.S. Ser. No. 09/707,395, filed on Nov. 7, 2000, entitled “MethodsFor Treating Pervasive Development Disorders”, both of which arecommonly owned and incorporated herein by reference.

[0047] It has also been discovered by the present inventor thatpopulations of autistic children suffer from GI disturbances and otherconditions which are dysautonomic in nature. Moreover, as explainedbelow, and in accordance with the present invention, it has beendiscovered by the inventor herein that a population of individualssuffering from dysautonomic disorders such as FD and Parkinson's haveabnormal or pathologic levels of pancreatic enzymes such as chymotrypsinin their stools. Thus, these findings are believed to indicate apossible link between the etiology of autism, ADD, ADHD and autonomicdysfunction. For example, it is postulated that in dysautonomicsyndromes, the partial paresis of the gastrointestinal tract, andtherefore the lack of functioning of the secretory cells of the proximalsmall intestine, preclude the proper formation and or release ofsecretin. It is further postulated that this abnormal protein digestionas reflected by the low levels of pancreatic enzymes such aschymotrypsin, can be improved by the administration of secretin, CCK,VIP, other neuropeptides, peptides and/or digestive enzymes to therebyameliorate the symptomotologies of dysautonomic conditions. Indeed, aslow measures of fecal chymotrypsin, for example, expresses anabnormality of protein digestion and/or pancreatic dysfunction, it ispostulated that an improvement of protein digestion to promote normalgrowth and development of an individual suffering from a dysautonomicdisorder or dysautonomic condition by the administration of secretin,CCK, VIP, other neuropeptides and/or peptides and/or digestive enzymes,can ameliorate the dysautonomic symptomatologies.

[0048] The following case studies support the above findings. Further,preferred methods for diagnosing and treating dysautonomic disorders anddyautonomic conditions in accordance with the invention are described.It is to be understood that these examples are set forth by way ofillustration only, and nothing therein shall be taken as a limitationupon the overall scope of the invention.

[0049] Case 1

[0050]FIG. 1 is a diagram of a family tree over four generations of afamily known for having Parkinson's, SIDS and ADD/ADHD and learningdisabilities. As shown, each of the generations 1 through 4 demonstratea related condition. In generation 1, one parent had Parkinson'sdisease. In generation 2, A1 has Parkinson's disease. In generation 3,A2 and A3 suffered from tremors for 2 and 1 years, respectively. Ingeneration 4, A4 has ADHD and is learning disabled, A5 suffers fromAspergers (a form of PDD) and A6 suffered from SIDS. The family treedemonstrates a connection between dysautonomia, SIDS and ADD/ADHD. It ispostulated that if Parkinson's, SIDS and FFI could result from aprolonged QT interval, and that these dysautonomic conditions could belinked together, the fecal chymotrypsin levels, for example, would beabnormal.

[0051] Certain members of the family in FIG. 1.(i.e., A1, A2, A4 and A5)were examined by analyzing their fecal chymotrypsin. In a preferredembodiment, a fecal chymotrypsin test comprises the following steps.First, approximately 2 grams of stool is collected from an individualand placed in a sterile container (although it is to be understood thatany quantity of stool may be collected, as 2 grams of stool is not arequired amount). The stool sample is analyzed using, e.g., an enzymaticphotospectrometry analysis as is known by those skilled in the art, todetermine the level of fecal chymotrypsin in the stool. Although theenzymatic photospectrophotometry process is preferred, any suitableconventional method may be used for measuring fecal chymotrypsin.

[0052] After determining the chymotrypsin level in a stool sample, thechymotrypsin level is compared with a normal threshold chymotrypsinlevel. By way of example, with the fecal chymotrypsin tests of the stoolsamples being performed at 30 degrees C., normal levels of chymotrypsinare deemed to lie above 8.4 U/gram, whereas pathologically abnormallevels are deemed to lie below 4.2 U/gram. In addition, a chymotrypsinlevel between 8.4 U/gram and 4.2 U/gram is considered equivocal, andfurther testing of the individual's fecal chymotrypsin levels over aperiod of time should be performed. In another embodiment, the thresholdchymotrypsin level is based on a level of chymotrypsin associated withat least one other individual of the same approximate age that does nothave the dysautonomic disorder.

[0053] Using the above fecal chymotrypsin test, the results were asfollows. A1, A2, A4 and A5 each demonstrated abnormal fecal chymotrypsinlevels, 0.1 U/gm, 1.6 U/gm, 2.2 U/gm and 1.8 U/gm, respectively. Thefecal chymotrypsin of A3 and A6 were not tested.

[0054] Case 2

[0055] A 6 year old male child previously diagnosed with FamilialDysautonomia presents with marked autonomic dysfunction, including atotal inability to walk or talk. The child lacked fine motor movements,and underwent an autonomic crisis 5-7 times per day, which necessitatedcontinuous skilled nursing, with life support equipment including arespirator in close proximity. The child was fed with a food pump, andhad to have his bowel evacuated by hand due to the near totalanestitzation of the small and large intestines. Fundal Plication wasperformed in order to deduce the incidence of reflux, and excessivedrooling was continually present. The child was completely dependentupon his care givers, and was classified during his first year of lifeas having autistic qualities.

[0056] The child was administered ongoing secretin infusions. Apreferred secretin infusion process includes the initial step ofprepping an arm of the individual with an IV injection of saline. A testdose of 1 U of, e.g., Secretin-Ferring is then administered to theindividual. Approximately one minute after infusion, the indivudual isexamined for signs of allergic reaction including rash, increased heartrate, and increase of blood pressure. If the individual does not displayany signs of allergic reaction, the remaining units of Secretin-Ferringis administered to the individual in the manner of an IV push, which isthen followed by a saline flush. Subsequently, the individual receives a1-2 U/kg of body weight infusion of Secretin-Ferring via an IV pushmethod approximately every 4 weeks for 8 months.

[0057] It is to be understood that any commercially available form ofsecretin may be used. Furthermore, treatment of a dysautonomic conditioncan be made by the administration of an effective amout of secretin,neuropeptide, CCK,VIP, peptides and or digestive enzymes through one ofintravenous, transdermal, intranasal, small molecule or a combinationthereof, or other siutable methods of administration.

[0058] After the 4th secretin administration, the child began to exhibitsignificant changes in his behavior as well as significant changes inhis autonomic dysfunction. The child began to walk and utter words. Hisloss of blood pressure and autonomic crises became non-existent, hisneed for a nurse practitioner was completely eliminated, and he was ableto work with an aide who helped him ambulate.

[0059] Case 3

[0060] A child diagnosed as having FD was administered a fecalchymotrypsin test using the test described above on a stool sampleobtained from the child comprising about 2 grams of stool. As shown inFIG. 2, the initial fecal chymotrypsin level of the child was determinedto be 0.3 U/gram, which falls significantly below the preferred normalthreshold of 8.4 U/gram. The child was administered a 1-2 U/kg of bodyweight infusions of Secretin-Ferring via an IV push method over a 20week period and stool samples were analyzed either pre or post infusion.The results shown in FIG. 2 demonstrate that the child's fecalchymotrypsin level progressively increased with the secretin infusions.

[0061] Case 4

[0062] The fecal chymotrypsin of 10 adults with previously diagnosedParkinson's Disease were analyzed using the test described above.Further, 4 adults and 2 children with other dysautonomic conditionsincluding diabetic autonomic failure, orthostatic intolerance syndrome,Familial dysautonomia and HSAN III were administered a fecalchymotrypsin test, and 13 adults the same age with no known conditionwere administered a fecal chymotrypsin test.

[0063] As shown in FIG. 3, 9 out of 10 Parkinson's patients had abnormalfecal chymotrypsin levels. Each of the age matched adults did notexhibit an abnormal fecal chymotrypsin level. All 4 patients with otherdysautonomic conditions exhibited an abnormal fecal chymotrypsin level(e.g., below 8.4 U/gm). All 13 normal subjects had fecal chymotrypsinlevels within the normal range.

[0064] Case 5

[0065] 4 children were administered secretin in the amount of 1 U/kg.Table 1 below demonstrates the changes observed where “BP” denotes isblood pressure and FC dentotes fecal chymotrypsin level. As shown inTable 1, a significant decrease in blood pressure was observed in eachchild immediately after the administration of secretin. Additionally, aflush similar to that of niacin was observed in 3 children. TABLE 1 BPChild AGE FC prior 1 min 5 min 10 min observations 1 4 1.7 120/70 90/6095/65 100/65  Facial flush 2 2 3.3 110/80 80/50 90/60 90/60 Whole bodyflush 3 6 2.0 130/85 100/70  100/70  105/85  Sweating 4 6 2.6 120/6090/50 95/50 100/70  Facial flush

[0066] Case 6

[0067] 2 adults were administered secretin in the amount of 1 U/kg.Table 2 below demonstrates the changes reported. Adult #2 reportedhaving some hypertension prior to the administration of secretin. Shereported having no difficulty with her hypertension for 6 months postadministration. TABLE 2 Adult AGE BP Prior 1 Min 10 Min Description 1 33110/70  90/70 100/65 Facial Flush 2 29 135/85 100/70 100/70 Facial flush

[0068] In summary, the results of the case studies described hereindemonstrate that dysautomonic disorders may be treated with theadmininstration of secretin, CCk, VIP, and other neuropeptides andpeptides and/or digestive enzymes. Furthermore, the results indicatethat the quantitative level or activity of pancreatic enzymes in a stoolsample, such as fecal chymotrypsin, can be used to determine if anindividual has, or can develop, one or more dysautonomic disorders orconditions. Further, pancreatic enzymes such as chymotrypsin can be usedas biological markers to determine the efficacy of administeringsecretin, CCk, VIP, and other neuropeptides and peptides and/ordigestive enzymes to an individual having a dysautonomic disorder orcondition to thereby treat the individual. Indeed, the above casestudies indicate that the administration of secretin, CCK, VIP, andother neuropeptides and peptides and/or digestive enzymes to suchindividuals having, for example, sub-normal to pathologic levels offecal chymotrypsin, will result in the amelioration of symptomatologiesof such disorders.

[0069] Although illustrative embodiments have been described herein withreference to the accompanying drawings, it is to be understood that thepresent invention is not limited to those precise embodiments, and thatvarious other changes and modifications may be affected therein by oneskilled in the art without departing from the scope or spirit of theinvention. All such changes and modifications are intended to beincluded within the scope of the invention as defined by the appendedclaims.

What is claimed is:
 1. A method for treating a dyautonomic disorder withsecretin, the method comprising the step of administering to anindividual having the disorder an effective amount of secretin toimprove a symptom of the disorder.
 2. The method of claim 1, furthercomprising the step of analyzing a compound in a stool sample of theindividual, wherein the administration of secretin is based on theanalysis of the stool sample.
 3. The method of claim 1, wherein thecompound comprises a pancreatic enzyme.
 4. The method of claim 1,wherein the pancreatic enzyme comprises chymotrypsin.
 5. The method ofclaim 4, wherein the step of analyzing the stool sample comprises thesteps of: measuring a quantitative level of chymotrypsin present in thestool sample; and comparing the measured quantitative level with atleast one threshold chymotrypsin level to determine the efficacy ofsecretin administration to the individual.
 6. The method of claim 5,wherein the at least one threshold chymotrypsin level is based on alevel of chymotrypsin associated with at least one other individual ofthe same approximate age that does not have the disorder.
 7. The methodof claim 5, wherein the at least one threshold chymotrypsin level isapproximately 8.4 U/gm.
 8. The method of claim 5, wherein the at leastone threshold chymotrypsin level is approximately 4.2 U/gm.
 9. Themethod of claim 1, wherein the disorder comprises Familial dysautonomia(Riley-Day Syndrome).
 10. The method of claim 1, wherein the disordercomprises Parkinson's disease.
 11. The method of claim 1, wherein thedisorder comprises a disorder of the catecholamine dysfunction.
 12. Themethod of claim 1, wherein the disorder comprise baroreflex failure. 13.The method of claim 1, wherein the disorder comprise dopamine-BHydroxylase deficiency.
 14. The method of claim 1, wherein the disordercomprises familial paraganglioma syndrome.
 15. The method of claim 1,wherein the disorder comprises aromatic-L-amino acid decarboxylasedeficiency.
 16. The method of claim 1, wherein the disorder comprisesMenke's disease.
 17. The method of claim 1, wherein the disordercomprises tetrahydrobiopterin deficiency.
 18. The method of claim 1,wherein the disorder comprises a monoamine oxidase deficiency state. 19.The method of claim 1, wherein the disorder comprises a catecholaminetype tumor or lesion as a pheochromocytoma chemodectina or neuroblasoma.20. The method of claim 1, wherein the disorder comprises HereditarySensory and autonomic neuropathy type III (HSAN III).
 21. The method ofclaim 1, wherein the disorder comprises a central autonomic disordertype.
 22. The method of claim 1, wherein the disorder comprises multiplesystem atrophy (Shy-Drager syndrome).
 23. The method of claim 1, whereinthe disorder comprise an orthostatic intolerance syndrome.
 24. Themethod of claim 1, wherein the disorder comprises mitral valve prolapse.25. The method of claim 1, wherein the disorder comprises posturaltachycardia syndrome (POTS).
 26. The method of claim 1, wherein thedisorder comprises idiopathic hypovolemia.
 27. The method of claim 1,wherein the disorder comprises a disorder of dopamine metabolism. 28.The method of claim 1, wherein the disorder comprises a disorder of thecardiovascular system.
 29. The method of claim 1, wherein the disordercomprises hypertension.
 30. The method of claim 1, wherein the disordercomprise Gullain-Barre syndrome (acute idiopathic polyneuropathy). 31.The method of claim 1, wherein the disorder comprises Chaga's disease.32. The method of claim 1, wherein the disorder comprises pure autonomicfailure.
 33. The method of claim 1, wherein the disorder comprisesdiabetic autonomic failure.
 34. The method of claim 1, wherein thedisorder comprise a mitochondrial disease.
 35. The method of claim 1,wherein the disorder comprises syncope.
 36. The method of claim 1,wherein the disorder comprises renal disease.
 37. The method of claim 1,wherein the disorder comprises fetal fatal insomnia.
 38. The method ofclaim 1, wherein the disorder comprises Sudden Infant Death Syndrome(SIDS).
 39. A method for treating a dyautonomic disorder or conditionwith peptides, the method comprising the step of administering to anindividual having the disorder an effective amount of peptides toimprove a symptom of the disorder.
 40. The method of claim 39, furthercomprising the step of analyzing a compound in a stool sample of theindividual, wherein the administration of peptides is based on theanalysis of the stool sample.
 41. The method of claim 39, wherein thecompound comprises a pancreatic enzyme.
 42. The method of claim 39,wherein the pancreatic enzyme comprises chymotrypsin.
 43. The method ofclaim 42, wherein the step of analyzing the stool sample comprises thesteps of: measuring a quantitative level of chymotrypsin present in thestool sample; and comparing the measured quantitative level with atleast one threshold chymotrypsin level to determine the efficacy ofpeptide administration to the individual.
 44. A method for treating adyautonomic disorder with digestive enzymes, the method comprising thestep of administering to an individual having the disorder an effectiveamount of digestive enzymes to improve a symptom of the disorder. 45.The method of claim 44, further comprising the step of analyzing acompound in a stool sample of the individual, wherein the administrationof digestive enzymes is based on the analysis of the stool sample. 46.The method of claim 44, wherein the compound comprises a pancreaticenzyme.
 47. The method of claim 44, wherein the pancreatic enzymecomprises chymotrypsin.
 48. The method of claim 47, wherein the step ofanalyzing the stool sample comprises the steps of: measuring aquantitative level of chymotrypsin present in the stool sample; andcomparing the measured quantitative level with at least one thresholdchymotrypsin level to determine the efficacy of digestive enzymeadministration to the individual.
 49. A method for determining if anindividual has, or can develop, a dysautonomic disorder or condition,comprising the steps of: obtaining a stool sample from the individual;analyzing a compound in the stool sample; and correlating the analysisof the compound with a dysautonomic disorder or condition or lackthereof.
 50. The method of claim 49, wherein the compound comprises apancreatic enzyme.
 51. The method of claim 49, wherein the compoundcomprises a digestive enzyme.
 52. The method of claim 49, wherein thecompound comprises chymotrypsin.
 53. The method of claim 49, wherein thestep of analyzing comprises the step of determining a quantity of thecompound in the stool sample.
 54. The method of claim 49, wherein thestep of correlating comprises the step of comparing the quantity of thecompound in the stool sample with a normal quantity of the compoundfound in an individual that does not have a dysautonomic disorder. 55.The method of claim 53, wherein the quantity of the compound in thestool is indicative of abnormal pancreatic function.
 56. The method ofclaim 53, wherein the quantity of the compound in the stool isindicative of abnormal protien digestion and metabolism.
 57. The methodof claim 49, wherein the compound in the stool is indicative of aninflammatory process.